Related Experiment Video
Updated: Jan 11, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
A preserved TGFβ cytostatic response through DLD-mediated metabolic modulation undermines anti-TGFβ therapy in
Yi-Qian Pan1, Yi Han1, Zheng-Yu Qian1
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, 510060, China.
Abstract:
Despite the well-known role of the transforming growth factor-β (TGFβ) pathway in cancer progression, therapies targeting it have largely failed in the clinic. This suggests our understanding of TGFβ's function is incomplete. Here we show that this therapeutic failure is rooted in a fundamental paradox: while TGFβ promotes malignant traits in gastric cancer, many cancer cells remain sensitive to its potent tumor-suppressive effects. We uncover that this suppression works by impairing the cell's energy metabolism through modulating dihydrolipoamide dehydrogenase (DLD). Therefore, broadly blocking the TGFβ pathway can inadvertently release a natural brake on tumor growth. Based on this insight, we demonstrate that co-targeting this metabolic vulnerability with an inhibitor (devimistat) alongside an anti-TGFβ agent significantly enhances therapeutic efficacy in gastric cancer models. This combination approach presents a promising strategy to overcome the limitations of current therapies.
Insights
Transforming growth factor-β (TGFβ) paradoxically suppresses gastric cancer by impairing metabolism via dihydrolipoamide dehydrogenase (DLD). Targeting this metabolic vulnerability with devimistat and anti-TGFβ agents enhances therapy.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- The transforming growth factor-β (TGFβ) pathway is crucial in cancer, but targeted therapies have shown limited clinical success.
- A deeper understanding of TGFβ's complex roles, including its tumor-promoting and tumor-suppressive functions, is needed.
- Gastric cancer exhibits a paradox where TGFβ drives malignancy yet retains suppressive effects on cancer cells.
Purpose of the Study:
- To investigate the underlying mechanisms of TGFβ's paradoxical effects in gastric cancer.
- To identify therapeutic strategies that overcome the limitations of current TGFβ-targeted treatments.
- To explore the role of cellular metabolism in TGFβ-mediated tumor suppression.
Main Methods:
- Analysis of TGFβ pathway signaling in gastric cancer models.
- Investigation of metabolic alterations induced by TGFβ, focusing on dihydrolipoamide dehydrogenase (DLD).
- Evaluation of combination therapy using an anti-TGFβ agent and a metabolic inhibitor (devimistat) in preclinical models.
Main Results:
- TGFβ's tumor-suppressive effect in gastric cancer is mediated by the inhibition of cellular energy metabolism through DLD modulation.
- Broadly blocking the TGFβ pathway can release this metabolic suppression, potentially promoting tumor growth.
- Combined inhibition of TGFβ and the metabolic vulnerability with devimistat significantly improved therapeutic efficacy in gastric cancer models.
Conclusions:
- The therapeutic failure of anti-TGFβ agents may stem from overlooking its metabolic suppression of cancer cells.
- Targeting the metabolic vulnerability associated with TGFβ signaling offers a promising strategy to enhance gastric cancer treatment.
- Combination therapy with anti-TGFβ agents and metabolic inhibitors like devimistat represents a novel approach to overcome treatment resistance.
Related Concept Videos
01:16TGF - β Signaling Pathway
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38Mitogens and the Cell Cycle